Type 2 diabetes is a public health epidemic in the United States, afflicting more than 20 million Americans. It is a complex disease with pathologic effects on numerous organ systems including central and autonomic nervous systems. Insulin resistance is a precursor to type 2 diabetes and is marked by a reduced sensitivity to insulin. A key network of the brain that is sensitive to insulin is the mesolimbic system. This network also plays a role in the control of autonomic function. Understanding how mesolimbic activity is altered in insulin resistance will help us understand pathways by which insulin resistance leads to autonomic dysregulation. The present study will recruit 11 individuals with insulin resistance and 11 individuals with normal insulin sensitivity. Participants will be screened by providing a fasting blood sample from which HOMA-IR values will be calculated. Qualifying participants will complete four clinical visits: (1) An initial screening visit, (2) A 2-hour oral glucose tolerance est, (3) An fMRI scan while in a fasting state, (4) An fMRI scan after consuming a mixed-meal preload. The fMRI scan will include a taste-reward task designed to evoke activity in the mesolimbic system. The goal of the present proposal is to identify functional alterations the mesolimbic system that occur in insulin resistance and may explain dysregulation in autonomic activity. Heart rate variability, a marker of autonomic regulation of the heart, will be recorded i the scanner and compared across days in conjunction with changes in resting brain activity. The applicant will receive training in the pathophysiology of diabetes, gain expertise in functional neuroimaging, and further study the central control of autonomic functioning. Training will include coursework, meetings with mentors and consultants, attendance of national conferences and local colloquia. The applicant will also gain experience in recruiting participants, collecting data, and writing scientific papers. This research will inform and influence the diabetes literatur by integrating the role of the central nervous system in the pathology of the autonomic nervous system that often accompanies type 2 diabetes. By using a within-subject design, the feasibility of the study is greatly increased such that a smaller participant sample can yield more reliable data. A more comprehensive understanding of the mechanisms that link insulin resistance to autonomic dysregulation, promises to guide the development of preventative strategies for slowing the progression from insulin resistance to type 2 diabetes. PUBLIC HEALTH RELEVANCE: Insulin resistance is a precursor to type 2 diabetes and alters the activity of the autonomic nervous system. The mesolimbic system of the brain is sensitive to insulin and is involved in the control of autonomic function. The proposed study will compare mesolimbic and autonomic activity between people with and without insulin resistance. This research will help understand pathways through which insulin resistance leads to complications of type 2 diabetes.